Disease relapse is a leading etiology of morbidity and mortality for patients with non-Hodgkin lymphoma (NHL) and autologous hematopoietic stem cell transplant following a myeloablative preparative regimen (auto-HSCT) can salvage only a subset of these patients. This Lymphoma SPORE Project 1 renewal resubmission seeks to develop targeted cellular immunotherapy capable of eradicating lymphoma posttransplant minimal residual disease (MRD) using CD19-specific T cell adoptive immunotherapy (AIT). Over the last funding cycle, we developed a genetic engineering approach to equip T cells with the ability to recognize and lyse tumor cells of B-cell lineage NHL using chimeric antigen receptors (CARs) specific for CD19 and initiated a first-in-human pilot clinical trial. Our initial clinical experience revealed a significant obstacle to achieving robust therapeutic activity; namely, that infused T cells survived only transiently in the tumor-bearing recipient. To address this critical issue, we elected to study the fate of adoptively transferred T cells using a non-human primate model that closely recapitulates clinical therapy in humans. These studies have revealed a key insight- that a rare population of T cells present in the circulation, the central memory T cell (TCM). is capable of high-level sustained engraftment following adoptive transfer. Accordingly, we have reconfigured our clinical T cell production platform to immunomagnetically purify CDS* TCM from peripheral blood mononuclear cell preparations. These CDS* TCM then undergo polyclonal activation, lentiviral vector transduction to express a CD19-specific scFvFc:^ CAR, and are expanded over a brief 21-day interval in IL- 2/IL-15 prior to cryopreservation. The first specific aim of the project seeks to demonstrate that CD19RCAR^ CDS* TcM-derived effector cells from NHL patients are phenotypically and functionally similar to those derived from healthy donors.
The second aim seeks to define the maximum tolerated dose (MTD) of CD19R-CAR*CD8* TcM-derived effector cells when infused shortly following auto-HSCT (Day +2) when patients with recurrent diffuse large cell lymphoma (DLCL) have minimal disease burdens and are profoundly lymphopenic from the transplant myeloablative preparative regimen. The third specific aim seeks to determine the magnitude and duration of persistence of transferred T cells in treated patients, the ability of transferred effector cells to revert to TMEM and populate memory T cell niches, and the anti-CD19 effector functioning of these cells in patients as determined by tracking the kinetics of CD19* B cell reconstitution. Lastly, we will seek to demonstrate the exportability of the approach by opening the trial to patient accrual both at the FHCRC in Seattle as well as City of Hope. Each of these Specific Aims focuses on key translational research objectives essential for moving the field of lymphoma AIT forward, including the conduct of a first-in-human trial using central memory T cell adoptive therapy. As such. Project 1 is fully aligned with the SPORE mandate for innovative translational research.
The studies proposed in Project 1 are focused on the development of new immunotherapeutic strategies to eradicate lymphoma MRD following auto-HSCT, a leading cause of morbidity and mortality facing patients with NHL. The technological advances in ex vivo TCM isolation, genetic modification and ex vivo propagation and the knowledge gained from the proposed clinical trial are expected to advance the field of adoptive T cell therapy for lymphoma and human malignancy in general.
|Herrmann, Andreas; Lahtz, Christoph; Nagao, Toshikage et al. (2017) CTLA4 Promotes Tyk2-STAT3-Dependent B-cell Oncogenicity. Cancer Res 77:5118-5128|
|Herrera, Alex F; Mei, Matthew; Low, Lawrence et al. (2017) Relapsed or Refractory Double-Expressor and Double-Hit Lymphomas Have Inferior Progression-Free Survival After Autologous Stem-Cell Transplantation. J Clin Oncol 35:24-31|
|Kortylewski, Marcin; Moreira, Dayson (2017) Myeloid cells as a target for oligonucleotide therapeutics: turning obstacles into opportunities. Cancer Immunol Immunother 66:979-988|
|Herrera, Alex F; Armand, Philippe (2017) Minimal Residual Disease Assessment in Lymphoma: Methods and Applications. J Clin Oncol 35:3877-3887|
|Won, Haejung; Moreira, Dayson; Gao, Chan et al. (2017) TLR9 expression and secretion of LIF by prostate cancer cells stimulates accumulation and activity of polymorphonuclear MDSCs. J Leukoc Biol 102:423-436|
|Gibson, Christopher J; Lindsley, R Coleman; Tchekmedyian, Vatche et al. (2017) Clonal Hematopoiesis Associated With Adverse Outcomes After Autologous Stem-Cell Transplantation for Lymphoma. J Clin Oncol 35:1598-1605|
|Herrera, Alex F; Rodig, Scott J; Song, Joo Y et al. (2017) Outcomes after Allogeneic Stem Cell Transplantation in Patients with Double-Hit and Double-Expressor Lymphoma. Biol Blood Marrow Transplant :|
|Urak, Ryan; Walter, Miriam; Lim, Laura et al. (2017) Ex vivo Akt inhibition promotes the generation of potent CD19CAR T cells for adoptive immunotherapy. J Immunother Cancer 5:26|
|Zhang, Chunyan; Xin, Hong; Zhang, Wang et al. (2016) CD5 Binds to Interleukin-6 and Induces a Feed-Forward Loop with the Transcription Factor STAT3 in B Cells to Promote Cancer. Immunity 44:913-923|
|Beharry, Andrew A; Lacoste, Sandrine; O'Connor, Timothy R et al. (2016) Fluorescence Monitoring of the Oxidative Repair of DNA Alkylation Damage by ALKBH3, a Prostate Cancer Marker. J Am Chem Soc 138:3647-50|
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